Methods for the preparation of alkyl diaryl borinates and complexed diarylboronic acids

ABSTRACT

The present invention provides methods for preparing complexed diaryl boronic acids from alkyl diarylborinates.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application Ser.No. 60/347,811, filed Jan. 9, 2002, the disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods for preparing alkyl diarylborinatesand methods for preparing complexed diarylboronic acids, which areuseful as antibacterial agents.

2. Description of the Related Art

N—O complexed diarylboronic acids are known to be effectivepharmaceutical agents. For example, such compounds are capable ofinhibiting adenine DNA methyltransferases in bacterial cells and thusexhibit antibacterial, growth-inhibitory properties against anybacterial species that produces an adenine DNA methyltransferase.Antibacterial diarylboronic acids are described in InternationalApplication Publication No. WO 00/75142.

Currently available methods for the preparation of N—O complexeddiarylboronic acids require the use of dichloroborane methyl sulfidecomplex as a starting material. The use of dichloroborane methyl sulfidecomplex has several disadvantages, including the formation of dimethylsulfide (DMS) as a side product of the reaction. Further, dichloroboranemethyl sulfide reacts violently with water to produce flammable andharmful gases and has a repugnant odor that causes great discomfort forany lab personnel working with the material.

The formation of DMS as a side product makes the process of isolating areaction product without contaminating the working area with DMSextremely difficult. Like dichloroborane methyl sulfide complex, DMSalso has a foul odor. Further, DMS is a cancer suspect agent.

A need exists, therefore, for a method for preparing N—O complexeddiarylboronic acids, and complexed diarylboronic acids in general, thatis safer, more versatile and friendlier to lab personnel than currentlyknown methods.

SUMMARY OF THE INVENTION

The present invention provides a method for preparing a compound of theformula I:

The invention also provides a method for preparing a compound of formulaIII:

The invention further provides compounds of formula I and formula IIIprepared according to the methods of the invention.

The methods of the invention are advantageous, inter alia, because theypermit efficient synthesis of alkyl diarylborinates using reagents thatare less toxic, less noxious and less dangerous than conventionalreagents used in these syntheses.

Specific preferred embodiments of the present invention will becomeevident from the following more detailed description of certainpreferred embodiments and the claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

As indicated above, the invention provides methods of preparingcompounds of formula I:

wherein A is N, O or S;

-   -   W is C_(p), where p is 0 or 1;    -   R^(a), R^(b), R^(c), R^(d), and R^(e) are the same or different        and are independently hydrogen, halogen, nitro, nitroso, lower        alkyl, aryl or substituted aryl, lower alkoxy, lower        alkoxyalkyl, or cycloalkyl or cycloalkyl alkoxy, where each        cycloalkyl group has from 3-7 members, where up to two of the        cycloalkyl members are optionally hetero atoms selected from        sulfur, oxygen and nitrogen, and where any member of the alkyl,        aryl or cycloalkyl group is optionally substituted with halogen,        lower alkyl or lower alkoxy, aryl or substituted aryl, halogen,        nitro, nitroso, aldehyde, carboxylic acid, amide, ester, or        sulfate, or wherein R^(a), R^(b), R^(c), R^(d), and R^(e) may be        connected by aromatic, aliphatic, heteroaromatic,        heteroaliphatic ring structures or substituted embodiments        thereof, where R^(a) is absent when A is O or S and R^(d) is        absent when p=0;    -   R^(f) is hydrogen or is absent; and        wherein    -   Ar¹ and Ar² can be the same or different and are each        independently thienyl, aryl or aryl substituted at one or a        plurality of positions with halogen, nitro, nitroso, lower        alkyl, aryl or substituted aryl, lower alkoxy, lower        alkoxyalkyl, or cycloalkyl or cycloalkyl alkoxy, where each        cycloalkyl group has from 3-7 members, where up to two of the        cycloalkyl members are optionally hetero atoms selected from        sulfur, oxygen and nitrogen, and where any member of the alkyl,        aryl or cycloalkyl group is optionally substituted with halogen,        lower alkyl or lower alkoxy, aryl or substituted aryl, halogen,        nitro, nitroso, aldehyde, carboxylic acid, amide, ester, or        sulfate, and        wherein    -   bond 1, bond 2, bond 3 and bond 4 are independently a single        bond or a double bond, provided that when A is S or O, bond 1 is        a single bond and where A is N, bond 1 is a double bond.

Compounds of formula I are useful as pharmaceutical agents. For example,compounds of formula I are antibacterial compounds, as described inInternational Application Publication No. WO 00/75142, and pending U.S.patent application Ser. No. 09/578,991, filed May 25, 2000, each ofwhich is incorporated herein by reference in its entirety.

The methods of the invention for preparing compounds of formula I aredepicted in Reaction Schemes 1 and 2.

-   -   M is, for example, MgBr or Li

Referring to Reaction Scheme 1, a trialkylborate is reacted withmetalloorganic reagents Ar¹M and Ar²M to form an alkyl diarylborinate offormula III. Preferably, the reaction is conducted by the addition ofthe trialkylborate to the metalloorganic reagents in an aprotic,non-aqueous solvent, such as tetrahydrofuran (THF) or diethyl ether.Also preferably, the addition is conducted under an inert atmosphere,such as a nitrogen or noble gas atmosphere, and at a temperature lowerthan room temperature, more preferably a temperature lower than 0° C.For example, the addition is advantageously conducted at −78° C. underargon gas.

Following completion, the reaction is worked up by either a non-acidicworkup step or by an acidic workup step. A non-acidic workup ispreferred. In a non-acidic workup, the reaction mixture is treated withan excess of an organic solvent, most preferably an alcohol solvent suchas methanol. The product is then isolated from the reaction mixture byknown methods, such as by removal of the solvent under vacuum, and thenthe alkyl boronate is extracted with an ether or other organic solventfrom the aqueous metal salts from the metalloorganic reagent. In theless preferred acidic workup step, an acidic solvent, such as dilutehydrochloric acid, is added to the reaction mixture to give a diarylboronic acid (Ar¹Ar²B—OH). The boronic acid is then converted to theborinate of formula III by treating the boronic acid with an alcoholsuch as methanol.

Metalloorganic reagents suitable for use in the methods of the inventioninclude Grignard reagents and organic alkali metal compounds, whereinthe alkali metal is lithium or sodium. Other metalloorganic reagents areknown in the art, such as zinc, copper and lithium metalloorganicreagents, can be used. A preferred metalloorganic reagent is a Grignardreagent. Grignard reagents are well known, and many are commerciallyavailable. Others can be readily prepared by known methods. At least twoequivalents of metalloorganic reagent are used for each equivalent ofalkylborate. A single metalloorganic reagent can be used (i.e., whereAr¹M and Ar²M in Scheme 1 are the same), thus yielding an alkyldiarylborinate Ar¹Ar²B—O-alkyl in which Ar¹ and Ar² are the same.Alternatively, two different metalloorganic reagents can be used,yielding an alkyl diarylborinate in which Ar¹ and Ar² are not the same.

Any alkylborate, B(O-Alkyl)₃, is suitable for use in the reactiondescribed above. Preferred alkylborates include lower alkyl boronates,comprising 1-6 carbon atoms per alkyl group. Examples of preferredalkylboronates include but are not limited to trimethylborate,triethylborate, tributylborate or mixtures thereof. A more preferredalkylborate is trimethylborate. Alkylborates are commercially available(for example from Sigma-Aldrich, Milwaukee, Wis.) or can be readilyprepared by known methods.

Referring to Reaction Scheme 2, the alkyl diarylborinate of formula IIIprepared as described in Reaction Scheme 1 is complexed with acomplexing agent of formula II. Preferably, the complexing step isperformed by dissolving or dispersing the complexing agent of formula IIin a solvent and adding the solution or dispersion to a solution ordispersion of the alkyl diarylborinate of formula III. The productcompound of formula I can be isolated by a variety of techniquesincluding crystallization and filtration, or removal of solvent invacuum. The product can be purified by known methods, includingrecrystallization, and/or chromatograhy.

The complexing agent II can be any compound containing an amino groupand either a hydroxy, a thiol or a second amino group. The amino groupand the hydroxy, thiol or second amino group are separated by 2 or 3carbon atoms. Examples of such complexing agents include:

wherein,

-   n is 1 or 2;-   R and R′ are the same or different and are independently hydrogen,    halogen, lower alkyl or lower alkoxy, aryl or substituted aryl,    halogen, nitro, nitroso, aldehyde, carboxylic acid, amide, ester, or    sulfate, and-   R₁, R₂, R₃, and R₄ are the same or different and are independently    hydrogen, halogen, nitro, nitroso, lower alkyl, aryl or substituted    aryl, lower alkoxy, lower alkoxyalkyl, or cycloalkyl or cycloalkyl    alkoxy, where each cycloalkyl group has from 3-7 members, where up    to two of the cycloalkyl members are optionally hetero atoms    selected from sulfur, oxygen and nitrogen, and where any member of    the alkyl, aryl or cycloalkyl group is optionally substituted with    halogen, lower alkyl or lower alkoxy, aryl or substituted aryl,    halogen, nitro, nitroso, aldehyde, carboxylic acid, amide, ester, or    sulfate, or R₁, R₂, R₃, and R₄ may be connected by aromatic,    aliphatic, heteroaromatic, heteroaliphatic ring structures or    substituted embodiments thereof.

Preferred compounds of Formula I prepared according to the methods ofthe invention include those wherein A is oxygen.

Preferred compounds of Formula I prepared according to the methods ofthe invention also include those wherein Ar¹=Ar².

Preferred compounds of Formula I prepared according to the methods ofthe invention also include those wherein Ar¹ and Ar² are selected from:

Preferred compounds of Formula II prepared according to the methods ofthe invention include:

The methods of the invention have several distinct advantages over otherprocedures for the preparation of complexed diarylboronic acids. Forexample, by using a trialkylborate as a starting material, chloroboranemethyl sulfide is not required and the concomitant formation of DMS as aside product is avoided. As a result, the process of isolating areaction product is greatly simplified. Additionally, whentrialkylborate reacts with water it produces alcohols, which arerelatively harmless substances compared with the reaction side productsproduced according to the prior art.

In an industrial setting where large quantities of reagents arerequired, trialkylborinates are more appealing starting materials thanthe previously used reagents, not only because of the inherent safety ofthe borinates, but also because of their cost. Trimethylborate, forexample, is considerably less expensive than previously used reagents.

The presence of an alkyl ester in compounds of formula III allows thiscompound to form a complex with a wider variety of complexing agents offormula II than was previously possible. This is due in part toincreased solubility of the compound of formula III and because there isa decreased possibility of side reactions and side products using thesecompounds. Previous methods for synthesizing complexed diarylboronicacids used a boronic acid in the complexing step. Boronic acids,however, can react with any amine (base) in the complexing agent toproduce a salt, which produces an undesired product. The boronic estersof formula III of the invention, on the other hand, can react with awider variety of compounds, including compounds containing hydrophilicor polar charged substituents, without producing such undesiredproducts.

A further advantage of the methods of the invention is thatdiarylborinates of formula III in the invention are prepared in a singlestep. Prior art methods prepared boronic acid in a first step andrequired a second step to produce the alkyl boronate, and are thus lessrobust than the instant methods.

Compounds of Formula I prepared according to the methods of theinvention may contain one or more asymmetric carbon atoms, so that thecompounds can exist in different stereoisomeric forms. These compoundscan be, for example, racemates or optically active forms. In thesesituations, the single enantiomers, i.e., optically active forms, can beobtained by asymmetric synthesis or by resolution of the racemates.Resolution of the racemates can be accomplished, for example, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography using, for example a chiral HPLCcolumn.

Compounds prepared according to the methods of the invention can existas tautomers in solution. When structures and names are given for onetautomeric form the other tautomeric form is also included in theinvention.

Representative compounds prepared according to the methods of thepresent invention include, but are not limited to the compoundsdisclosed herein and their pharmaceutically acceptable acid and baseaddition salts. In addition, if a compound is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

In the description of the reagents and methods of this invention,particular terms are defined as follows.

By “alkyl”, “lower alkyl”, and “C₁-C₆ alkyl” in the present invention ismeant straight or branched chain alkyl groups having 1-6 carbon atoms,such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,3-hexyl, and 3-methylpentyl.

By “alkoxy”, “lower alkoxy”, and “C₁-C₆ alkoxy” in the present inventionis meant straight or branched chain alkoxy groups having 1-6 carbonatoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy,n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy,neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

By the term “halogen” in the present invention is meant fluorine,bromine, chlorine, and iodine.

By “aliphatic ring” or “cycloalkyl”, e.g., C₃-C₇ cycloalkyl, in thepresent invention is meant cycloalkyl groups having 3-7 atoms such as,for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl. In the C₃-C₇ cycloalkyl groups, preferably in the C₅-C₇cycloalkyl groups, one or two of the carbon atoms forming the ring canoptionally be replaced with a heteroatom, such as sulfur, oxygen ornitrogen. Examples of such groups are piperidinyl, piperazinyl,morpholinyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl,azaperhydroepinyl, oxazaperhydroepinyl, oxepanyl, oxazaperhydroinyl, andoxadiazaperhydroinyl. C₃ and C₄ cycloalkyl groups having a memberreplaced by nitrogen or oxygen include aziridinyl, azetidinyl, oxetanyl,and oxiranyl.

By “aryl” is meant an aromatic carbocyclic group having a single ring(e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensedrings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which isoptionally mono-, di-, or trisubstituted with, e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy. Preferred aryl groups include phenyl andnaphthyl, each of which is optionally substituted as defined herein.

By “heteroaromatic” or “heteroaryl” is meant one or more aromatic ringsystems of 5-, 6-, or 7-membered rings containing at least one and up tofour heteroatoms selected from nitrogen, oxygen, or sulfur. Suchheteroaryl groups include, for example, thienyl, furanyl, thiazolyl,imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl,napthyridinyl, benzimidazolyl, and benzoxazolyl. Preferred heteroarylsare thiazolyl, pyrimidinyl, preferably pyrimidin-2-yl, and pyridyl.Other preferred heteroaryl groups include 1-imidazolyl, 2-thienyl, 1-,or 2-quinolinyl, 1-, or 2-isoquinolinyl, 1-, or 2-tetrahydroisoquinolinyl, 2- or 3-furanyl and 2-tetrahydrofuranyl.

By “aliphatic ring,” or “heterocycle,” is meant one or more carbocyclicring systems of 3-, 4-, 5-, 6-, or 7-membered rings which includes fusedring systems of 9-11 atoms containing at least one and up to fourheteroatoms selected from nitrogen, oxygen, or sulfur. Preferredheterocycles of the present invention include morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide,piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl,homopiperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl,dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,dihydrofuryl, dihydropyranyl, azepanyl, diazepanyl, tetrahydrothienylS-oxide, tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide.

Compounds prepared according to the methods of the invention can beprovided as pharmaceutical compositions. The pharmaceutical compositionscan be manufactured in a manner that is itself known, e.g., by means ofa conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or lyophilizingprocesses.

Pharmaceutical compositions can be formulated in conventional mannerusing one or more physiologically acceptable carriers comprisingexcipients and auxiliaries that facilitate processing of the activecompounds into preparations that can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfiric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitic, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)_(n)—CH₃ where nis 0-4, and the like. Non-toxic pharmaceutical base addition saltsinclude salts of bases such as sodium, potassium, calcium, ammonium, andthe like. Those skilled in the art will recognize a wide variety ofnon-toxic pharmaceutically acceptable addition salts.

For injection, the compounds prepared according to the methods of theinvention can be formulated in appropriate aqueous solutions, such asphysiologically compatible buffers such as Hanks's solution, Ringer'ssolution, or physiological saline buffer. For transmucosal andtranscutaneous administration, penetrants appropriate to the barrier tobe permeated are used in the formulation. Such penetrants are generallyknown in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained with solid excipient, optionally grinding aresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired, to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds can be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers can be added. All formulations fororal administration should be in dosages suitable for suchadministration. For buccal administration, the compositions can take theform of tablets or lozenges formulated in conventional manner.

For administration by inhalation, the compounds prepared according tothe methods of the invention are conveniently delivered in the form ofan aerosol spray presentation from pressurized packs or a nebuliser,with the use of a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitcan be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g., gelatin for use in an inhaler orinsufflator can be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds can be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection can be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionscan take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and can contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds can be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions can contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension can also contain suitablestabilizers or agents that increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.Alternatively, the active ingredient can be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use. The compounds can also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds canalso be formulated as a depot preparation. Such long acting formulationscan be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds can be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

A pharmaceutical carrier for hydrophobic compounds of formula I is acosolvent system comprising benzyl alcohol, a nonpolar surfactant, awater-miscible organic polymer, and an aqueous phase. The cosolventsystem can be the VPD co-solvent system. VPD is a solution of 3% w/vbenzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.The VPD co-solvent system (VPD:5W) consists of VPD diluted 1:1 with a 5%dextrose in water solution. This co-solvent system dissolves hydrophobiccompounds well, and itself produces low toxicity upon systemicadministration. Naturally, the proportions of a co-solvent system can bevaried considerably without destroying its solubility and toxicitycharacteristics. Furthermore, the identity of the co-solvent componentscan be varied: for example, other low-toxicity nonpolar surfactants canbe used instead of polysorbate 80; the fraction size of polyethyleneglycol can be varied; other biocompatible polymers can replacepolyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars orpolysaccharides can substitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds can be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Certainorganic solvents such as dimethylsulfoxide also can be employed,although usually at the cost of greater toxicity. Additionally, thecompounds can be delivered using a sustained-release system, such assemipermeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules can, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein and nucleic acidstabilization can be employed.

The pharmaceutical compositions also can comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

The compounds of Formula I can be provided as salts withpharmaceutically compatible counterions. Pharmaceutically compatiblesalts can be formed with many acids, including but not limited tohydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic,phosphoric, hydrobromic, sulfinic, formic, toluenesulfonic,methanesulfonic, nitic, benzoic, citric, tartaric, maleic, hydroiodic,alkanoic such as acetic, HOOC—(CH₂)_(n)—CH₃ where n is 0-4, and thelike. Salts tend to be more soluble in aqueous or other protonicsolvents that are the corresponding free base forms. Non-toxicpharmaceutical base addition salts include salts of bases such assodium, potassium, calcium, ammonium, and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

Pharmaceutical compositions of the compounds prepared according to themethods of the invention can be formulated and administered through avariety of means, including systemic, localized, or topicaladministration. Techniques for formulation and administration can befound in “Remington's Pharmaceutical Sciences,” Mack Publishing Co.,Easton, Pa. The mode of administration can be selected to maximizedelivery to a desired target site in the body. Suitable routes ofadministration can, for example, include oral, rectal, transmucosal,transcutaneous, or intestinal administration; parenteral delivery,including intramuscular, subcutaneous, intramedullary injections, aswell as intrathecal, direct intraventricular, intravenous,intraperitoneal, intranasal, or intraocular injections.

Alternatively, one can administer the compound in a local rather thansystemic manner, for example, via injection of the compound directlyinto a specific tissue, often in a depot or sustained releaseformulation.

Pharmaceutical compositions suitable for use include compositionswherein the active ingredients are contained in an effective amount toachieve its intended purpose. More specifically, a therapeuticallyeffective amount means an amount effective to prevent development of orto alleviate the existing symptoms of the subject being treated.Determination of the effective amounts is well within the capability ofthose skilled in the art, especially in light of the detailed disclosureprovided herein.

For administration to non-human animals, the drug or a pharmaceuticalcomposition containing the drug may also be added to the animal feed ordrinking water. It will be convenient to formulate animal feed anddrinking water products with a predetermined dose of the drug so thatthe animal takes in an appropriate quantity of the drug along with itsdiet. It will also be convenient to add a premix containing the drug tothe feed or drinking water approximately immediately prior toconsumption by the animal.

Preferred compounds prepared according to the methods of the inventionwill have certain pharmacological properties. Such properties include,but are not limited to oral bioavailability, low toxicity, low serumprotein binding and desirable in vitro and in vivo half-lives. Assaysmay be used to predict these desirable pharmacological properties.Assays used to predict bioavailability include transport across humanintestinal cell monolayers, including Caco-2 cell monolayers. Serumprotein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcová et al. (1996, J Chromat. B677: 1-27). Compound half-life is inversely proportional to thefrequency of dosage of a compound. In vitro half-lives of compounds maybe predicted from assays of microsomal half-life as described by Kuhnzand Gieschen (1998, DRUG METABOLISM AND DISPOSITION, vol. 26, pp.1120-1127).

Toxicity and therapeutic efficacy of such compounds can be determined byconventional pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD50 (the dose lethal to 50% of thepopulation) and the ED50 (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio between LD50and ED50. Compounds that exhibit high therapeutic indices are preferred.The data obtained from these cell culture assays and animal studies canbe used in formulating a range of dosage for use in humans. The dosageof such compounds lies preferably within a range of circulatingconcentrations that include the ED50 with little or no toxicity. Thedosage can vary within this range depending upon the dosage formemployed and the route of administration utilized. The exactformulation, route of administration and dosage can be chosen by theindividual physician in view of the patient's condition. (See, e.g.Fingl et al., 1975, in The Pharmacological Basis of Therapeutics, ch. 1,p. 1).

Dosage amount and interval can be adjusted individually to provideplasma levels of the active moiety that are sufficient to maintainbacterial cell growth-inhibitory effects. Usual patient dosages forsystemic administration range from 100-2000 mg/day. Stated in terms ofpatient body surface areas, usual dosages range from 50-910 mg/m²/day.Usual average plasma levels should be maintained within 0.1-1000:M. Incases of local administration or selective uptake, the effective localconcentration of the compound cannot be related to plasma concentration.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The following Examples are provided for the purposes of illustration andare not intended to limit the scope of the present invention. Thepresent invention is not to be limited in scope by the exemplifiedembodiments, which are intended as illustrations of individual aspectsof the invention. Indeed, various modifications of the invention inaddition to those shown and described herein will become apparent tothose skilled in the art from the foregoing description and accompanyingdrawings. Such modifications are intended to fall within the scope ofthe appended claims.

EXAMPLES Example 1 General Procedure for the Synthesis of MethylDiarylborinates

Trimethylborate (0.95 eq) is added dropwise to a freshly preparedsolution of aryl magnesium bromide (2 eq) in tetrahydrofuran (0.3 M)under argon at −78° C. The mixture is warmed to room temperature andstirred overnight. The solution is cooled to −78° C. and excess Grignardreagent is destroyed by the dropwise addition of methanol until no moreeffervescence is observed. Solvents are removed in vacuo and the residuedissolved in diethyl ether followed by a water wash. The organic layeris dried (over MgSO₄), filtered and the solvents removed in vacuo togive the product as a foam that can be used without furtherpurification. Any trialkylborate may be used as a substitute fortrimethylborate including triethylborate and tributylborate, asdiscussed above.

Example 2 General Procedure for the Synthesis of N—O ComplexedDiarylboronic Acids

The complexing agent (0.9 eq) is dissolved in methanol (ordichloromethane depending on solubility) and added to a solution ofmethyl diarylborinate (1 eq) (prepared as outlined above) in methanol.The solution is allowed to stand overnight, if the product hascrystallized, the solid is collected and washed with cold ethanol;otherwise the solvents are removed in vacuo to give a solid which ispurified by recrystallization from ethanol or diethyl ether (dependingon the complexing agent). If this is unsuccessful the product ispurified by column chromatography on silica gel eluting with diethylether/hexane.

Example 3 Synthesis of Methyl Di(p-chlorophenyl)borinate

Trimethylborate (2.2 ml, 1.92×10⁻² mol) is added dropwise to a freshlyprepared solution of p-chlorophenyl magnesium bromide (40.4 ml, 1 M,4.04×10⁻² mol) in tetrahydrofuran (60 ml) under argon at −78° C. Themixture is warmed to room temperature and stirred overnight. Thesolution is cooled to −78° C. and excess grignard reagent is destroyedby the dropwise addition of methanol until no more effervescence isobserved. The solvents are removed in vacuo and the residue dissolved indiethyl ether and washed with water. The organic layer is dried (MgSO₄),filtered and the solvents removed in vacuo to give methyldi(p-chlorophenyl)borinate (4.60 g, 92%) as a solid which was usedwithout further purification.

Example 4 Synthesis of Methyl Di(p-fluorophenyl)borinate

Trimethylborate (1.0 ml, 8.75×10⁻³ mol) is added dropwise to a freshlyprepared solution of p-fluorophenyl magnesium bromide (18.4 ml, 1 M,1.84×10⁻² mol) in tetrahydrofuran (30 ml) under argon at −78° C. Themixture is warmed to room temperature and stirred overnight. Thesolution is cooled to −78° C. and excess grignard reagent is destroyedby the dropwise addition of methanol until no more effervescence isobserved. The solvents are removed in vacuo and the residue dissolved indiethyl ether and washed with water. The organic layer is dried (MgSO₄),filtered and the solvents removed in vacuo to give methyldi(p-fluorophenyl)borinate (1.93 g, 89%) as a solid which was usedwithout further purification.

Example 5 Synthesis of Methyl Di(m-chlorophenyl)borinate

Trimethylborate (1.3 ml, 1.14×10⁻² mol) is added dropwise to a freshlyprepared solution of m-chlorophenyl magnesium bromide (48 ml, 0.5 M,2.39×10⁻² mol) in tetrahydrofuran (30 ml) under argon at −78° C. Themixture is warmed to room temperature and stirred overnight. Thesolution is cooled to −78° C. and excess grignard reagent is destroyedby the dropwise addition of methanol until no more effervescence isobserved. The solvents are removed in vacuo and the residue dissolved indiethyl ether and washed with water. The organic layer is dried (MgSO₄),filtered and the solvents removed in vacuo to givedi(m-chlorophenyl)borinate (3.2 g, 94%) as a solid which was usedwithout further purification.

Example 6 Di-(p-chlorophenyl)borinic Acid 5-nitro-8-hydroxyquinolineEster

5-Nitro-8-hydroxyquinoline (340 mg, 1.79×10⁻³) was added to a solutionof methyl di(p-chlorophenyl)borinate (500 mg, 1.89×10⁻³) indichloromethane. The solution turned dark yellow and was left to stirovernight. The solvent was removed in vacuo to give a solid, which waswashed with diethyl ether (20 ml) and recrystalized from ethanol to givethe title compound (630 mg, 83%) as a dark yellow solid.

Example 7 Di-(m-chlorophenyl)borinic Acid 8-hydroxyquinoline Ester

A solution of 8-hydroxyquinoline (2.03 g, 1.4×10⁻² mol) in ethanol (40ml) was added dropwise to methyl di(m-chlorophenyl)borinate (3.7 g,1.4×10⁻² mol) in ethanol (40 ml) at room temperature. A yellowprecipitation was observed and was left to stand overnight. The solidwas collected by filtration and washed with cold ethanol to yield thetitle product as a yellow solid; mp 144-145° C.; ¹H-NMR (360 MHz, C²H₃₀²H): δ 8.83 (d, J=5.0 Hz, 1H), 8.63 (d, J=8.2 Hz, 1H), 7.78 (dd, J=8.6,5.0 Hz, 1H), 7.67 (t, J=8.2, 1H), 7.36 (d, J=8.2, 1H), 7.26-7.09 (m,9H); MS (+ve ESI) m/z 377 ([M+H]⁺, ¹⁰B, ³⁵Cl, ³⁵CI), 378 ([M+H]⁺, ¹¹B,³⁵Cl, ³⁵Cl), 379 ([M+H]⁺, ¹⁰B, ³⁵Cl, ³⁵Cl), 380 ([M+H]⁺, ¹⁰B, ³⁵Cl,³⁷Cl), 381 ([M+H]⁺, ¹⁰B, ³⁵Cl, ³⁵Cl), 382 ([M+H]⁺, ¹¹B, ³⁷Cl, ³⁷CI);Anal. (C₂₁H₁₄NOBCl₂)C, H, N.

Example 8 Di-(p-chlorophenyl)borinic Acid Glycine Ester

A solution of glycine (67 mg, 8.99×10⁻⁴ mol) in water (5 ml) was addeddropwise to a solution of methyl di(p-chlorophenyl)borinate (250 mg,9.47×10⁻⁴ mol) in ethanol (5 ml). The mixture was left to stirovernight. The solvents were removed in vacuo to give a solid, which waswashed with diethyl ether (40 ml) and recrystalized from ethanol to givethe title compound (225 mg, 82%) as a white solid.

Example 9 Di-(p-chlorophenyl)borinic Acid (L)-proline Ester

A solution of (L)-proline (54 mg, 4.69×10⁴ mol) in water (5 ml) wasadded dropwise to a solution of methyl di(p-chlorophenyl)borinate (130mg, 4.92×10⁴ mol) in ethanol (5 ml). The mixture was left to stirovernight. The solvents were removed in vacuo to give a solid, which waswashed with diethyl ether (40 ml) and recrystalized from ethanol to givethe title compound (149 mg, 90%) as a white solid.

Example 10 Di-(p-chlorophenyl)borinic Acid N-hydroxyethyl Cytosine Ester

A solution of N-hydroxyethyl cytosine (100 mg, 7.04×10⁻⁴ mol) in water(5 ml) was added dropwise to a solution of methyldi(p-chlorophenyl)borinate (205 mg, 7.75×10⁻⁴ mol) in ethanol (5 ml).The mixture was left to stir overnight. The solvents were removed invacuo to give a solid, which was washed with diethyl ether (30 ml) andrecrystalized from ethanol to give the title compound (211 mg, 79%) as awhite solid.

Example 11 Di-(p-chlorophenyl)borinic Acid N-hydroxyethyl5-fluorocytosine Ester

A solution of N-hydroxyethyl-5-fluorocytosine (364 mg, 2.27×10⁻³ mol) inwater (5 ml) was added dropwise to a solution of methyldi(p-chlorophenyl)borinate (659 mg, 2.50×10⁻³ mol) in ethanol (20 ml).The mixture was left to stir overnight. The solvents were removed invacuo to give a solid, which was washed with diethyl ether (40 ml) andrecrystalized from ethanol to give the title compound (773 mg, 86%) as awhite solid.

The following compounds are prepared according to the methods of theinvention: Example No. Compound 12

di-(p-fluorophenyl)borinic acid 8-hydroxyquinoline ester 13

di-(p-chlorophenyl)borinic acid 8-hydroxyquinoline ester 14

diphenylborinic acid 8-hydroxyquinoline ester 15

di-(p-fluorophenyl)borinic acid ethanolamine ester 16

di-(p-chlorophenyl)borinic acid ethanolamine ester 17

6-N-(diphenylborinic ester)-ethyl-adenine 18

6-N-(diphenylborinic ester)-ethyl-9-(2-(4-morpholinyl)-ethyl)-adenine 19

6-N-(diphenylborinicester)-ethyl-9-(3-(N-phthaloyl)-aminopropyl)-adenine 20

6-N-(diphenylborinicester)-ethyl-9-(2-(2-(2-hydroxyethoxy)ethoxy)-ethyl)-adenine 21

6-N-(diphenylborinic ester)-ethyl-9-(ethyl-2-acrylate)-methyl-adenine 22

Di-(4-chloro-2-fluorophenyl)borinic acid 8-hydroxyquinoline ester 23

Di-(3,4-methylenedioxyphenyl)borinic acid 8-hydroxyquinoline ester 24

Di-(4-methoxyphenyl)borinic acid 8-hydroxyquinoline ester 25

Di-(2-thienyl)borinic acid 8-hydroxyquinoline ester 26

Di-(p-fluorophenyl)borinic acid 8-hydroxyquinaldine ester 27

Di-(p-chlorophenyl)borinic acid 8-hydroxyquinaldine ester 28

Di-(4-methoxyphenyl)borinic acid 8-hydroxyquinaldine ester 29

Di-(p-fluorophenyl)borinic acid 5-chloro-8-hydroxyquinoline ester 30

Di-(p-chlorophenyl)borinic acid 5-chloro-8-hydroxyquinoline ester 31

Di-(3,4-methylenedioxyphenyl)borinic acid 5-chloro-8-hydroxyquinolineester 32

Di-(4-methoxyphenyl)borinic acid 5-chloro-8-hydroxyquinoline ester 33

Di-(3,4-methylenedioxyphenyl)borinic acid 8-hydroxy-5-nitroquinolineester 34

Diphenylborinic acid 2-aminophenol 35

Diphenylborinic acid pyridine-2-methanol 36

Diphenylborinic acid 2-amino-1-phenylpropanol 37

Diphenylborinic acid (S)-(+)-pyrrolidine-2-methanol 38

Di-(4-fluorophenyl)borinic acid ethanolamine ester 39

Di-(4-chlorophenyl)borinic acid ethanolamine ester 40

6-N-(diphenylborinic ester)-ethyl-9-(2-hydroxymethyl-5-methyl-tetrahydro-furan-3,4-diol)-adenine 41

6-amino-4(2-diphenylborinic ester) ethylamino pyrimidine 42

4-amino-5(2-diphenylborinic ester ethyliminoester)imidazole.

It should be understood that the foregoing disclosure emphasizes certainspecific embodiments of the invention and that all modifications oralternatives equivalent thereto are within the spirit and scope of theinvention as set forth in the appended claims.

1. A method for preparing a compound of formula I:

wherein A is N, O or S; W is C_(p), where p is 0 or 1; R^(a), R^(b),R^(c), R^(d), and R^(e) are the same or different and are independentlyhydrogen, halogen, nitro, nitroso, lower alkyl, aryl or substitutedaryl, lower alkoxy, lower alkoxyalkyl, or cycloalkyl or cycloalkylalkoxy, where each cycloalkyl group has from 3-7 members, where up totwo of the cycloalkyl members are optionally hetero atoms selected fromsulfur, oxygen and nitrogen, and where any member of the alkyl, aryl orcycloalkyl group is optionally substituted with halogen, lower alkyl orlower alkoxy, aryl or substituted aryl, halogen, nitro, nitroso,aldehyde, carboxylic acid, amide, ester, or sulfate, or wherein R^(a),R^(b), R^(c), R^(d), and R^(e) may be connected by aromatic, aliphatic,heteroaromatic, heteroaliphatic ring structures or substitutedembodiments thereof, where R^(a) is absent when A is O or S, and R^(d)is absent when p=0; R^(f) is hydrogen or is absent; and wherein Ar¹ andAr² can be the same or different and are each independently thienyl,aryl or aryl substituted at one or a plurality of positions withhalogen, nitro, nitroso, lower alkyl, aryl or substituted aryl, loweralkoxy, lower alkoxyalkyl, or cycloalkyl or cycloalkyl alkoxy, whereeach cycloalkyl group has from 3-7 members, where up to two of thecycloalkyl members are optionally hetero atoms selected from sulfur,oxygen and nitrogen, and where any member of the alkyl, aryl orcycloalkyl group is optionally substituted with halogen, lower alkyl orlower alkoxy, aryl or substituted aryl, halogen, nitro, nitroso,aldehyde, carboxylic acid, amide, ester, or sulfate, and wherein bond 1,bond 2, bond 3 and bond 4 are independently a single bond or a doublebond, provided that when A is S or O, bond 1 is a single bond and whereA is N, bond 1 is a double bond, said method comprising the step of:reacting an alkyl diarylborinate of formula III with a compound offormula II to form the compound of formula I


2. The method of claim 1 wherein the alkyl diarylborinate of formula IIIand the compound of formula II are in a ratio of about 1 to about 0.9equivalents respectively.
 3. The method of claim 1 wherein the compoundof formula III is:

wherein, n is 1 or 2; R and R′ are the same or different and areindependently hydrogen, halogen, lower alkyl or lower alkoxy, aryl orsubstituted aryl, halogen, nitro, nitroso, aldehyde, carboxylic acid,amide, ester, or sulfate, and R₁, R₂, R₃, and R₄ are the same ordifferent and are independently hydrogen, halogen, nitro, nitroso, loweralkyl, aryl or substituted aryl, lower alkoxy, lower alkoxyalkyl, orcycloalkyl or cycloalkyl alkoxy, where each cycloalkyl group has from3-7 members, where up to two of the cycloalkyl members are optionallyhetero atoms selected from sulfur, oxygen and nitrogen, and where anymember of the alkyl, aryl or cycloalkyl group is optionally substitutedwith halogen, lower alkyl or lower alkoxy, aryl or substituted aryl,halogen, nitro, nitroso, aldehyde, carboxylic acid, amide, ester, orsulfate, or R₁, R₂, R₃, and R₄ may be connected by aromatic, aliphatic,heteroaromatic, heteroaliphatic ring structures or substitutedembodiments thereof.
 4. The method of claim 1 wherein the alkyldiarylborinate of formula III is prepared by reacting a trialkylboratewith a metalloorganic reagent.
 5. The method of claim 4 wherein thetrialkylborate is trimethylborate, triethylborate, tributylborate, ormixtures thereof.
 6. The method of claim 4 wherein the metalloorganicreagent is a Grignard reagent or a lithium reagent.
 7. The method ofclaim 4 wherein the trialkylborate and the metalloorganic reagent are ina ratio of about 1 to about 2 equivalents respectively.
 8. The method ofclaim 4 further comprising the step of treating the reaction productwith methanol.
 9. A method for preparing a compound of formula III:

wherein Ar and Ar can be the same or different and are eachindependently aryl or aryl substituted at one or a plurality ofpositions with halogen, nitro, nitroso, lower alkyl, aryl or substitutedaryl, lower alkoxy, lower alkoxyalkyl, or cycloalkyl or cycloalkylalkoxy, where each cycloalkyl group has from 3-7 members, where up totwo of the cycloalkyl members are optionally hetero atoms selected fromsulfur, oxygen and nitrogen, and where any member of the alkyl, aryl orcycloalkyl group is optionally substituted with halogen, lower alkyl orlower alkoxy, aryl or substituted aryl, halogen, nitro, nitroso,aldehyde, carboxylic acid, amide, ester, or sulfate, said methodcomprising the step of reacting a trialkylborate with a metalloorganicreagent.
 10. The method of claim 9 wherein the trialkylborate istrimethylborate, triethylborate, tributylborate, or mixtures thereof.11. The method of claim 9 wherein the metalloorganic reagent is aGrignard reagent or a lithium reagent.
 12. The method of claim 9 whereinthe trialkylborate and the metalloorganic reagent are in a ratio ofabout 1 to about 2 equivalents respectively.
 13. The method of claim 9further comprising the step of treating the reaction product withmethanol.
 14. A compound of the formula I prepared by the method ofclaim
 1. 15. A compound of the formula III prepared by the method ofclaim
 9. 16. A compound according to claim 14 that is:Di-(p-chlorophenyl)borinic acid 5-nitro-8-hydroxyquinoline ester,Di-(m-chlorophenyl)borinic acid 8-hydroxyquinoline ester,Di-(p-chlorophenyl)borinic acid glycine ester,Di-(p-chlorophenyl)borinic acid (L)-proline ester,Di-(p-chlorophenyl)borinic acid N-hydroxyethyl cytosine ester,Di-(p-chlorophenyl)borinic acid N-hydroxyethyl 5-fluorocytosine ester,di-(p-fluorophenyl)borinic acid 8-hydroxyquinoline ester,di-(p-chlorophenyl)borinic acid 8-hydroxyquinoline ester,diphenylborinic acid 8-hydroxyquinoline ester,di-(p-fluorophenyl)borinic acid ethanolamine ester,di-(p-chlorophenyl)borinic acid ethanolamine ester, 6-N-(diphenylborinicester)-ethyl-adenine, 6-N-(diphenylborinicester)-ethyl-9-(2-(4-morpholinyl)-ethyl)-adenine, 6-N-(diphenylborinicester)-ethyl-9-(3-(N-phthaloyl)-aminopropyl)-adenine,6-N-(diphenylborinicester)-ethyl-9-(2-(2-(2-hydroxyethoxy)ethoxy)-ethyl)-adenine,6-N-(diphenylborinic ester)-ethyl-9-(ethyl-2-acrylate)-methyl-adenine,Di-(4-chloro-2-fluorophenyl)borinic acid 8-hydroxyquinoline ester,Di-(3,4-methylenedioxyphenyl)borinic acid 8-hydroxyquinoline ester,Di-(4-methoxyphenyl)borinic acid 8-hydroxyquinoline ester,Di-(2-thienyl)borinic acid 8-hydroxyquinoline ester,Di-(p-fluorophenyl)borinic acid 8-hydroxyquinaldine ester,Di-(p-chlorophenyl)borinic acid 8-hydroxyquinaldine ester,Di-(4-methoxyphenyl)borinic acid 8-hydroxyquinaldine ester,Di-(p-fluorophenyl)borinic acid 5-chloro-8-hydroxyquinoline ester,Di-(p-chlorophenyl)borinic acid 5-chloro-8-hydroxyquinoline ester,Di-(3,4-methylenedioxyphenyl)borinic acid 5-chloro-8-hydroxyquinolineester, Di-(4-methoxyphenyl)borinic acid 5-chloro-8-hydroxyquinolineester, Di-(3,4-methylenedioxyphenyl)borinic acid8-hydroxy-5-nitroquinoline ester, Diphenylborinic acid 2-aminophenol,Diphenylborinic acid pyridine-2-methanol, Diphenylborinic acid2-amino-1-phenylpropanol, Diphenylborinic acid(S)-(+)-pyrrolidine-2-methanol, Di-(4-fluorophenyl)borinic acidethanolamine ester, Di-(4-chlorophenyl)borinic acid ethanolamine ester.6-N-(diphenylborinicester)-ethyl-9-(2-hydroxymethyl-5-methyl-tetrahydro-furan-3,4-diol)-adenine,6-amino-4(2-diphenylborinic ester)ethylamino pyrimidine, or4-amino-5(2-diphenylborinic ester ethyliminoester)imidazole.